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Study · Animal study (in vivo) · mouse · 2025

4 results

The Heart Has Intrinsic Ketogenic Capacity that Mediates NAD+ Therapy in HFpEF.

Koay YC, McIntosh B, Ng YH, Cao Y, Wang XS, Han Y, Tomita S, Bai AY, Hunter B, Misra A, Loughrey CM, Bannon PG and 5 more

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Lal S, Lusis AJ, Kaye DM, Larance M, O'Sullivan JF

Circulation research11 Apr 2025Cited by 14 (Europe PMC)

PMID40211954 (opens in a new tab)PMCIDPMC12063684 (opens in a new tab)DOI10.1161/circresaha.124.325550 (opens in a new tab)PepBankPUB-40211954
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Summary

BackgroundHeart failure with preserved ejection fraction (HFpEF) has overtaken heart failure with reduced ejection fraction as the leading type of heart failure globally and is marked by high morbidity and mortality rates, yet with only a single approved pharmacotherapy: SGLT2i (sodium-glucose co-transporter 2 inhibitor). A prevailing theory for the mechanism underlying SGLT2i is nutrient deprivation signaling, of which ketogenesis is a hallmark. However, it is unclear whether the canonical ketogenic enzyme, HMGCS2 (3-hydroxy-3-methylglutaryl-coenzyme A synthase 2), plays any cardiac role in HFpEF pathogenesis or therapeutic response.MethodsWe used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.ResultsWe demonstrate, for the first time, the intrinsic capacity of the human heart to produce ketones via HMGCS2. We found that increased acetylation of HMGCS2 led to a decrease in the enzyme's specific activity. However, this was overcome by an increase in the steady-state levels of protein. Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF. Critically, using a conditional, cardiomyocyte-specific HMGCS2 knockdown murine model, we revealed that the oxidized form of nicotinamide adenine dinucleotide is unable to rescue HFpEF in the absence of cardiomyocyte HMGCS2.ConclusionsThe canonical ketogenic enzyme, HMGCS2, mediates the therapeutic effects of the oxidized form of nicotinamide adenine dinucleotide repletion in HFpEF by restoring normal lipid metabolism and mitochondrial function.
CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study4

3 results from studies that gave the peptide. No result from this study comes from people.

  1. 01AnimalAnimal study (in vivo)Efficacy outcome

    In HFpEF experimental models, oxidized nicotinamide adenine dinucleotide repletion rescued cardiac function.

    In plain wordsIn experimental HFpEF models, NAD+ repletion restored heart function.

    Peptide
    NAD+ (nicotinamide adenine dinucleotide)
    Outcome
    IncreaseCardiac function
    Study

    mousen: not reported in source

    HFpEF model
    Outcome group
    Heart function · Cardiovascular
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF.
    1 context sentence
    Summary · context
    We used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.
  2. 02AnimalOther designMechanism

    In HFpEF experimental models, oxidized nicotinamide adenine dinucleotide repletion restored HMGCS2 function through deacetylation.

    In plain wordsIn experimental HFpEF models, NAD+ repletion restored HMGCS2 function through deacetylation.

    Peptide
    NAD+ (nicotinamide adenine dinucleotide)
    Outcome
    IncreaseHMGCS2 function
    Study

    n: not reported in source

    HFpEF experimental models
    Outcome group
    Heart function · Cardiovascular
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF.
    1 context sentence
    Summary · context
    We used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.
  3. 03AnimalOther designMechanism

    In HFpEF experimental models, oxidized nicotinamide adenine dinucleotide repletion increased fatty acid oxidation.

    In plain wordsIn experimental HFpEF models, NAD+ repletion increased fatty acid oxidation.

    Peptide
    NAD+ (nicotinamide adenine dinucleotide)
    Outcome
    IncreaseFatty acid oxidation
    Study

    n: not reported in source

    HFpEF experimental models
    Outcome group
    Mitochondrial function · Cardiovascular
    Studied dose
    Dose not stated

    Source sentences

    Summary
    Oxidized form of nicotinamide adenine dinucleotide repletion restored HMGCS2 function via deacetylation, increased fatty acid oxidation, and rescued cardiac function in HFpEF.
    1 context sentence
    Summary · context
    We used human myocardium, human HFpEF and heart failure with reduced ejection fraction transcardiac blood sampling, an established murine model of HFpEF, ex vivo Langendorff perfusion, stable isotope tracing in isolated cardiomyocytes, targeted metabolomics, proteomics, lipidomics, and a novel cardiomyocyte-specific conditional HMGCS2-deficient model that we generated.

Studies that did not test the peptide alone1

In this study, NAD+ (nicotinamide adenine dinucleotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking NAD+ (nicotinamide adenine dinucleotide).

  1. 04AnimalNot a test of NAD+ (nicotinamide adenine dinucleotide) aloneAnimal study (in vivo)Mechanism

    In mice with cardiomyocyte-specific HMGCS2 knockdown, oxidized nicotinamide adenine dinucleotide could not rescue HFpEF.

    In plain wordsIn mice lacking heart-cell HMGCS2, NAD+ could not restore heart function in HFpEF.

    Peptide
    NAD+ (nicotinamide adenine dinucleotide)
    Outcome
    No significant changeHMGCS2-dependent cardiac rescue
    Study

    mousen: not reported in source

    cardiomyocyte-specific HMGCS2 knockdown HFpEF mouse model
    Outcome group
    Heart function · Cardiovascular

    Source sentences

    Summary
    Critically, using a conditional, cardiomyocyte-specific HMGCS2 knockdown murine model, we revealed that the oxidized form of nicotinamide adenine dinucleotide is unable to rescue HFpEF in the absence of cardiomyocyte HMGCS2.

    In this study, NAD+ (nicotinamide adenine dinucleotide) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking NAD+ (nicotinamide adenine dinucleotide).

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

  1. Version 2Current

    14 Oct 2026, 05:02 UTC

    Study results updated

  2. Version 1

    14 Oct 2026, 01:46 UTC

    First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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